CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells

Yu Tzu Tai, Ender Soydan, Weihua Song, Mariateresa Fulciniti, Kihyun Kim, Fangxin Hong, Xian Feng Li, Peter Burger, Matthew J. Rumizen, Sabikun Nahar, Klaus Podar, Teru Hideshima, Nikhil C. Munshi, Giovanni Tonon, Ruben D. Carrasco, Daniel E H Afar, Kenneth C. Anderson

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

CS1 is highly expressed on tumor cells from the majority of multiple myeloma (MM) patients regardless of cytogenetic abnormalities or response to current treatments. Furthermore, CS1 is detected in MM patient seraandcorrelates with active disease. However, its contribution to MM pathophysiology is undefined. We here show that CS1 knockdown using lentiviral short-interfering RNAdecreased phosphorylation of ERK1/2, AKT, and STAT3, suggesting that CS1 induces central growth and survival signaling pathways in MM cells. Serum deprivation markedly blocked survival at earlier time points in CS1 knockdown compared with control MM cells, associated with earlier activation of caspases, poly(ADP-ribose) polymerase, and proapoptotic proteins BNIP3 and BIK. CS1 knockdown further delayed development of MM tumor and prolonged survival in mice. Conversely, CS1 overexpression promoted myeloma cell growth and survival by significantly increasing myeloma adhesion to bone marrow stromal cells (BMSCs) and enhancing myeloma colony formation in semisolid culture. Moreover, CS1 increased c-maf-targeted cyclin D2-dependent proliferation, -integrin βl7/αE-mediated myeloma adhesion toBMSCs,and -vascular endothelial growth factor-induced bone marrow angiogenesis in vivo. These studies provide direct evidence of the role of CS1 in myeloma pathogenesis, define molecular mechanisms regulating its effects, and further support novel therapies targeting CS1 in MM.

Original languageEnglish
Pages (from-to)4309-4318
Number of pages10
JournalBlood
Volume113
Issue number18
DOIs
Publication statusPublished - 2009

Fingerprint

Cell adhesion
Multiple Myeloma
Mesenchymal Stromal Cells
Cell Adhesion
Tumors
Bone
Adhesion
Cyclin D2
Phosphorylation
Poly(ADP-ribose) Polymerases
Cell growth
Growth
Caspases
Integrins
Vascular Endothelial Growth Factor A
Chemical activation
Cells
Survival
Proteins
Chromosome Aberrations

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells. / Tai, Yu Tzu; Soydan, Ender; Song, Weihua; Fulciniti, Mariateresa; Kim, Kihyun; Hong, Fangxin; Li, Xian Feng; Burger, Peter; Rumizen, Matthew J.; Nahar, Sabikun; Podar, Klaus; Hideshima, Teru; Munshi, Nikhil C.; Tonon, Giovanni; Carrasco, Ruben D.; Afar, Daniel E H; Anderson, Kenneth C.

In: Blood, Vol. 113, No. 18, 2009, p. 4309-4318.

Research output: Contribution to journalArticle

Tai, YT, Soydan, E, Song, W, Fulciniti, M, Kim, K, Hong, F, Li, XF, Burger, P, Rumizen, MJ, Nahar, S, Podar, K, Hideshima, T, Munshi, NC, Tonon, G, Carrasco, RD, Afar, DEH & Anderson, KC 2009, 'CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells', Blood, vol. 113, no. 18, pp. 4309-4318. https://doi.org/10.1182/blood-2008-10-183772
Tai, Yu Tzu ; Soydan, Ender ; Song, Weihua ; Fulciniti, Mariateresa ; Kim, Kihyun ; Hong, Fangxin ; Li, Xian Feng ; Burger, Peter ; Rumizen, Matthew J. ; Nahar, Sabikun ; Podar, Klaus ; Hideshima, Teru ; Munshi, Nikhil C. ; Tonon, Giovanni ; Carrasco, Ruben D. ; Afar, Daniel E H ; Anderson, Kenneth C. / CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells. In: Blood. 2009 ; Vol. 113, No. 18. pp. 4309-4318.
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abstract = "CS1 is highly expressed on tumor cells from the majority of multiple myeloma (MM) patients regardless of cytogenetic abnormalities or response to current treatments. Furthermore, CS1 is detected in MM patient seraandcorrelates with active disease. However, its contribution to MM pathophysiology is undefined. We here show that CS1 knockdown using lentiviral short-interfering RNAdecreased phosphorylation of ERK1/2, AKT, and STAT3, suggesting that CS1 induces central growth and survival signaling pathways in MM cells. Serum deprivation markedly blocked survival at earlier time points in CS1 knockdown compared with control MM cells, associated with earlier activation of caspases, poly(ADP-ribose) polymerase, and proapoptotic proteins BNIP3 and BIK. CS1 knockdown further delayed development of MM tumor and prolonged survival in mice. Conversely, CS1 overexpression promoted myeloma cell growth and survival by significantly increasing myeloma adhesion to bone marrow stromal cells (BMSCs) and enhancing myeloma colony formation in semisolid culture. Moreover, CS1 increased c-maf-targeted cyclin D2-dependent proliferation, -integrin βl7/αE-mediated myeloma adhesion toBMSCs,and -vascular endothelial growth factor-induced bone marrow angiogenesis in vivo. These studies provide direct evidence of the role of CS1 in myeloma pathogenesis, define molecular mechanisms regulating its effects, and further support novel therapies targeting CS1 in MM.",
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T1 - CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells

AU - Tai, Yu Tzu

AU - Soydan, Ender

AU - Song, Weihua

AU - Fulciniti, Mariateresa

AU - Kim, Kihyun

AU - Hong, Fangxin

AU - Li, Xian Feng

AU - Burger, Peter

AU - Rumizen, Matthew J.

AU - Nahar, Sabikun

AU - Podar, Klaus

AU - Hideshima, Teru

AU - Munshi, Nikhil C.

AU - Tonon, Giovanni

AU - Carrasco, Ruben D.

AU - Afar, Daniel E H

AU - Anderson, Kenneth C.

PY - 2009

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N2 - CS1 is highly expressed on tumor cells from the majority of multiple myeloma (MM) patients regardless of cytogenetic abnormalities or response to current treatments. Furthermore, CS1 is detected in MM patient seraandcorrelates with active disease. However, its contribution to MM pathophysiology is undefined. We here show that CS1 knockdown using lentiviral short-interfering RNAdecreased phosphorylation of ERK1/2, AKT, and STAT3, suggesting that CS1 induces central growth and survival signaling pathways in MM cells. Serum deprivation markedly blocked survival at earlier time points in CS1 knockdown compared with control MM cells, associated with earlier activation of caspases, poly(ADP-ribose) polymerase, and proapoptotic proteins BNIP3 and BIK. CS1 knockdown further delayed development of MM tumor and prolonged survival in mice. Conversely, CS1 overexpression promoted myeloma cell growth and survival by significantly increasing myeloma adhesion to bone marrow stromal cells (BMSCs) and enhancing myeloma colony formation in semisolid culture. Moreover, CS1 increased c-maf-targeted cyclin D2-dependent proliferation, -integrin βl7/αE-mediated myeloma adhesion toBMSCs,and -vascular endothelial growth factor-induced bone marrow angiogenesis in vivo. These studies provide direct evidence of the role of CS1 in myeloma pathogenesis, define molecular mechanisms regulating its effects, and further support novel therapies targeting CS1 in MM.

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